WVU researchers unite in search of new drug to treat lung cancer

NSCLC comprises 85 percent of lung cancers. It often develops slowly and causes few or no symptoms until it has advanced. Because of this, only an approximate 25 percent of NSCLC cases are discovered at stages 1 or 2.

“We’ve got a diverse set of expertise that’s going to come together to try to solve one problem — how to develop inhibitors and place them clinically for targeting Ero1-α,” Dr. Hazlehurst, co-leader of the Alexander B. Osborn Hematopoietic Malignancy and Transplantation at the WVU Cancer Institute and professor of pharmaceutical sciences at the WVU School of Pharmacy, said.

Hazlehurst found that high expression of an enzyme called Ero1-α is a poor prognostic indicator of survival in lung cancer. Enzymes act as catalysts, increasing the rate of chemical reactions within cells. She hypothesizes that decreasing the activity of Ero1-α will make a tumor more susceptible to immunotherapy and that, as such, Ero1-α is a promising target for new drug development.

But first, the target needs to be validated. That’s a crucial step in the drug discovery process, and it ensures that the substance being evaluated is directly involved in a disease mechanism, and that modulating it is likely to have some therapeutic effect.

Robust target validation is accomplished in different ways — genetically, pharmacologically, pathologically — and to this end, Hazlehurst has assembled the following team of experts:

— Medicinal chemist Werner Geldenhuys, Ph.D., M.S., professor in the WVU School of Medicine, School of Pharmacy, and the WVU Rockefeller Neuroscience Institute

— Thoracic oncologist Mohammed Almubarak, M.D., associate professor of hematology/oncology

— Surgical oncologist Brian Boone, M.D., assistant professor of surgical oncology

— Pathologist Matthew Smoklin, M.D., associate professor of pathology, anatomy, and laboratory medicine

— Biostatistician Sinjin Wen, Ph.D., M.S., M.A., associate professor in the School of Public Health

The team is taking a three-pronged approach to validating Ero1-α’s role in lung cancer. The first aim is to genetically validate the target. Hazlehurst, a cancer pharmacologist, will use genetic editing to knock out Ero1-α in tumor cells in mice, and then test whether the tumors are more susceptible to immunotherapy.

“That gives you a real cause and effect,” Hazlehurst said, “but genetically knocking it out is probably not a tractable clinical strategy. So, the second aim is to see if we can pharmacologically validate the target.”

Dr. Geldenhuys will use structure-based drug design methods to develop specific, potent chemical inhibitors of Ero1-α. Hazlehurst will then test the most promising inhibitor in the tumor cells of the mice.

Hazlehurst’s findings suggest that high Ero1-α levels in a tumor may predict a poor response to immunotherapy, but “looking at cell lines doesn’t always replicate what you find in patients,” she said.

For the third aim, Drs. Almubarak, Boone, Smolkin, and Wen will use tumor tissues from primary lung cancer patients residing in West Virginia to test the extent to which levels of Ero1-α in a tumor predict response to immunotherapy. The hope is that it may be a useful tool to help determine lines of treatment.

“We are trying to put the pieces together for a roadmap to develop inhibitors,” Hazlehurst said, noting that the diversity of expertise in the team will allow for a wide range of training possibilities for INBRE-eligible students, and that data from the project will position the team for grants that can further support their collaboration.

Editor’s note: The use of animals in this project was evaluated by the WVU Institutional Animal Care and Use Ethics Committee. WVU is voluntarily accredited by AAALAC, a national peer organization that establishes a global benchmark for animal well-being in science.